DE19627310A1 - Imidazole derivatives as nitric oxide synthase inhibitors - Google Patents

Abstract

Compounds having the formulas (I) and (Ia) are disclosed, as well as their preparation and use in medicaments.

Description

The invention relates to cyclopentenyl and thienyl imidazole derivatives and their Manufacture and use in medicines.

It is known that imidazole derivatives have moderate to good affinity bind enzymes containing hemoglobin. From the literature it is known that with the enzymes Hemoglobin group in the active center belongs to nitric oxide synthase (NOS), and that Imidazole and some of its derivatives bind to it. This applies in particular to Phenylimidazoles, cf. on this: a) Wolff DJ; Gribin BJ .; Interferon gamma inducible murine macrophage nitric oxide synthase, Archives of Biochemistry and Biophys 1994 Jun; 311 (2): 293-299; b) Wolff DJ; Datto GA; Samatovicz R.A .; Calmodulin-dependent nitric-oxide synthase, J Biol Chem 1993, 268, 9430-9436, c) loc. Cit. 9425-9229; d) Moore, P.K. et al, 1- (2-trifluoromethylphenyl) imiduzole, a potent inhibitor of neuronal nitric oxide synthase; Br. J. Pharmacology 1995, 116, 2349.

It has now been found that the affinity of imidazole derivatives for NOS is not can be predictably increased if they carry suitable substituents. Compounds are obtained which are selective in very low concentrations (IC₅₀) inhibit inducible, human nitric oxide synthase (hiNOS) and with Excellent effectiveness in vivo. The affinity for others Isoforms of the enzyme NOS are less pronounced.

The selective nitric oxide synthase inhibitors are suitable as drugs for the treatment of diseases of the central nervous system such as multiple sclerosis in all forms, Alzheimer's disease, HIV dementia, amyotrophic lateral sclerosis and comparable sclerotic diseases, cerebral ischemia and others neurodegenerative diseases, including those related to inflammation to be brought. They are also suitable for the treatment of diseases such as sepsis or septic shock, hypotension, ARDS (adult respiratory distress syndrome), rheumatoid arthritis, osteoarthritis, of insulin-dependent diabetes mellitus (IDDM), inflammatory pelvic / bowel disease, meningitis, Glomerulonephritis, acute and chronic liver diseases, diseases caused by Rejection (for example allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis to name a few.

The invention relates to the compounds of the formula I or Ia:

wherein
Z sulfur or -NH-,
A GH₂ or a bond,
R¹ phenyl or a 5-membered hetaryl radical with 1-3 N, O or S atoms, each with halogen, cyano, C _1-4 alkyl, NH₂, -N (C _1-4 allyl) ₂ or -NH (C _1-4 alkyl) may be substituted, halogen, S (O) _m -CH₂R³ or OR⁴,
R² is hydrogen, optionally substituted with R phenyl, optionally substituted with R pyridinyl, halogen, cyano, NO₂, NH₂ or C _1-6 alkyl,
R = halogen, OH, NO₂, NH₂, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, NH (C _1-4 alkyl), -N (C _1-4 -Alkyl) ₂, NHSO₂-C _1-4 -alkyl, -COOH, -COOC _1-6 -alkyl, -CONHR⁵, -CF₃, -C (NH) -NHR⁶, -NH-C (NH) NHR⁷, -CH₂ -NHR⁸,
m = 0, 1, 2,
R³-R⁸ identically or differently means hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-7 cycloalkyl and their isomers, tautomers and physiologically acceptable salts.

Examples of heteroaryl radicals R 1 are: 2-furanyl, 2-thienyl, 3-thienyl, 1- Pyyrolyl, 1-pyrazolyl. 1-imidazolyl, 1, 2, 4-triazol-1-yl, 2-thiazolyl, thiodiazolyl, 2,3- Dihydrothiophenyl.

Alkyl is to be understood in each case as a straight-chain or branched alkyl radical, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, Hexyl.

Alkenyl contains in particular C _2-6 alkenyl radicals, which can be straight-chain or branched, such as 2-propenyl, 2-butenyl, 3-methyl-2-propenyl, 1-propenyl, 1-butenyl, vinyl.

As alkynyl radicals are, in particular, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl with 2-4 Suitable carbon atoms.  

C _3-7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in particular C _3-5 cycloalkyl.

Halogen means fluorine, chlorine, bromine and iodine.

The salts which are physiologically compatible are more organic and inorganic Suitable acids such as the readily soluble oxalates, Maleate, citrate, fumarate, acetate, lactates, tosylates, mesylates, phosphates, hydrochlorides Hydrobromides, tartrates, sulfates and others.

The compounds of the general formula I and Ia also include the possible ones tautomeric forms and in the case of double bonds include the E and Z isomers or, if there is a chiral center, the racemates or enantiomers.

The substituent -A-R1 is preferably in the adjacent position to the imidazole Basic structure. In the case of compounds of type I, imidazole and -A-R1 are preferably on the Double bond.

The compounds of formula I or Ia and their physiologically tolerable salts are due to their affinity for and inhibition of the effects of nitric oxide Synthases and especially the inducible nitric oxide synthase as Medicinal products can be used. Because of their active profile, the inventive ones are suitable Compounds for the treatment of diseases caused by excess nitrogen monoxide evoked in the body under inducing and pathological conditions or be reinforced.

These include multiple sclerosis, Alzheimer's disease, HIV dementia, amyotrophs Lateral sclerosis and comparable sclerotic diseases, cerebral ischemia and other neurodegenerative diseases associated with inflammation will. They are also suitable for the treatment of cardiovascular diseases Systems such as sepsis or septic shock, ARDS (adult respiratory distress syndrome), rheumatoid arthritis, osteoarthritis, of insulin-dependent diabetes mellitus (IDDM), inflammatory pelvic / bowel disease, meningitis, Glomerulonephritis, acute and chronic liver diseases, diseases caused by Rejection (for example allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.  

For the use of the compounds according to the invention as medicaments, these are brought into the form of a pharmaceutical preparation that in addition to the active ingredient for enteral or parenteral application suitable pharmaceutical, organic or anor ganic inert carrier materials, such as water, gelatin, gum arabic, Milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, for example as tablets, Dragees, suppositories, capsules or in liquid form, for example as solutions, Suspensions or emulsions are present. If necessary, they also contain Auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for Change in osmotic pressure or buffer.

For parenteral use in particular, injection solutions or Suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, suitable.

Surfactant auxiliaries such as salts of the Bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can be used.

For oral use in particular tablets, coated tablets or capsules are included Talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch. The application can also be in liquid form, such as for example as a juice, to which a sweetener may be added.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the Patients, type and severity of the disease to be treated and similar factors vary ieren. The daily dose is 1-2000 mg, preferably 20-500 mg, the dose being as Single dose to be administered once or divided into 2 or more daily doses can be given.

The compound of the invention is prepared in accordance with known methods Methods. For example, compounds of formula I or Ia are obtained in that one

• a) a compound of formula II or IIa wherein
  -AR¹, R² and Z have the above meaning and Flu is a leaving group, in the presence of a base with imidazole, or
• b) a compound of formula III or IIIa wherein Z and A are as defined above and Hal represents halogen, substituted in the presence of a base or with an organometallic compound and then halogenated or selectively reduced if necessary or forming thioether or cleaving ether or saponifying nitriles or esterifying or amidating acids or etherifying from phenols or Esters are synthesized or amino groups are exchanged or boiled using the Sandmeyer reaction, or sulfides are oxidized to sulfones or sulfoxides, or sulfoxides are reduced to sulfides, or amines are converted to amides or sulfonamides, or alkylated or decarboxylated, or isomers are separated or salts are formed.

Flu can be, for example, tosylate, mesylate, triflate, nonaflate or halogen mean. The aromatic is increased in the presence of bases at room temperature or higher Temperature implemented in aprotic solvents. In places, the implementation facilitates or improves yield when copper or copper salts are added will.  

The bases include, for example, alkali compounds such as potassium carbonate, Sodium hydroxide, alkali alcoholates such as potassium tert-butylate and in particular metal hydrides suitable as sodium hydride. Sometimes the connections can also be made under Phase transfer conditions are implemented. You get mixtures of compounds with the substituent imidazolyl in different numbers and or in different Positions are separated in the usual way.

Suitable solvents for the reaction are aprotic polar solvents such as Dimethylformamide, N-methylpyrrolidone or DMSO or other comparable.

If the reaction is carried out appropriately, both the escape group and an additional group can existing halogen atom can be substituted.

If the reaction is carried out with organometallic compounds, then Grignard compounds, optionally with transition metal catalysis, stannyl compounds or palladium-catalyzed coupling with boronic acid derivatives.

Halogen or nitro can be introduced by bromination or nitration, where if necessary, the reactivity of the aromatic substituents already present note is. The base body may have to be nitrided or halogenated before using a heterocycle is implemented. The nitro group can then be reduced and the resulting amino group exchanged via Sandmeyer reaction or boiled to phenol or alkylated, and the resulting hydroxy compounds can be etherified or to be esterified. By nucleophilic substitution of leaving groups such as bromides Thioether produced, these sulfides can then be oxidized to sulfones or sulfoxides will. Nitriles are saponified and, if necessary, acids are esterified or amidated.

Any subsequent saponification of an ester group can be basic or, if necessary, acidic, by up to at room temperature or elevated temperature to the boiling point of the reaction mixture in the presence of alkali metal hydroxides Ethanol or other alcohols or by means of acids such as. For example, hydrochloric acid hydrolyzed and optionally processed further imidazolium salts.

The carboxylic acid is esterified in a manner known per se Diazomethane or the corresponding alcohol in acid or in the presence of a activated acid derivative. Activated acid derivatives include, for example, acid chloride, -imidazolide or anhydride in question.  

The amidation takes place on the free acids or on their reactive derivatives as in for example, acid chlorides, mixed anhydrides, imidazolides or azides Reaction with the corresponding amines at room temperature or higher Temperature.

In addition, a nitro group or Halogen, especially bromine, are introduced. This creates mixtures that are substituted May contain 5-ring heterocycles and are separated in the usual way. When a Nitrile is present, this can be saponified by known methods or in the Corresponding amine, tetrazole or amidoxime can be converted.

The nitro group or possibly the cyano group is reduced to the amino group catalytically in polar solvents at room temperature or elevated temperature below Hydrogen pressure. Precious metal catalysts such as palladium or platinum are used as catalysts optionally suitable in the presence of barium sulfate or on supports such as coal. Instead of Hydrogen can also be used ammonium formate in a known manner. Reducing agents such as zinc in aqueous ammonium chloride solution or acetic acid, tin-II- Chloride or titanium III chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts.

If an alkylation of an amino group is desired, it can be carried out by customary methods for example, alkylated with alkyl halides.

The cyano group can be introduced using the Sandmeyer reaction; for example, one can use the intermediates from the amino compounds with nitrites react the diazonium salts formed with alkali metal cyanides in the presence of Cu-I-cyanide.

The introduction of the halogens chlorine, bromine or iodine via the amino group can also according to Sandmeyer by using the diazonium salts formed intermediately with nitrites with Cu (I) chloride or Cu (I) bromide in the presence of the corresponding acid such as hydrochloric acid or reacting hydrobromic acid or reacting with potassium iodide.

The introduction of a NO₂ group succeeds through a number of known Nitriding methods. For example, inert with nitronium tetrafluoroborate Solvents such as halogenated hydrocarbons or in sulfolane or glacial acetic acid be nitrided. The introduction of z. B. by nitrating acid in water or conc. Sulfuric acid as a solvent at temperatures between 0 ° C and 30 ° C.  

The isomer mixtures can by conventional methods such as Crystallization, chromatography or salt formation in the enantiomers or E / Z isomers be separated.

The salts are prepared in a conventional manner by adding a solution to the Compound of formula I or Ia with the equivalent amount or an excess of one Acid, which is optionally in solution, is added and the precipitate is separated off or in works up the solution in the usual way.

As far as the preparation of the starting compounds is not described, these are known or analogous to known compounds or processes described here producible. 5-Tributylstannyl-2,3-dihydrothiophene was as in Synlett 1995, p. 1053 get described.

The compounds were made by one or more of the following methods characterized: melting point, mass spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR). NMR spectra were recorded using a Bruker 300 MHz device measured, the (deuterated) solvents are given and as follows abbreviated: CDCl₃ (chloroform), DMSO (dimethyl sulfoxide). Shifts are in delta and ppm. Also mean: THF (tetrahydrofuran), DME (dimethoxyethane), DMF (N, N-dimethylformamide), NMP (N-methylpyrrolidone), EE (ethyl acetate). All solvents are p.A. quality, unless otherwise noted. All reactions are under protective gas unless it is an aqueous solution. It means: [m] g ([milli] grams), m (multiplet, multiple signals), s (singlet), d (doublet), dd (double doublet etc.), tr (triplet), H (hydrogen protons), Hz (Hertz), ml (milliliters), RT (room temperature). Melting points are given in degrees Celsius and are not corrected. The yields in percent relate to the educt, not to sales.

The following examples like the structures according to the invention and their production demonstrate.

example 1 1- (cyclopenten-1-yl) imidazole, 1- (2-bromocyclopenten-1-yl) imidazole, and 1- (2- [imidazol-1-yl] - cyclopenten-1-yl) imidazole

1.12 g of 1,2-dibromocyclopentene are dissolved in 1 ml of NMP, 2 equivalents of imidazole, 2.2 equivalents of potassium carbonate and 50 mg of copper powder are added and the mixture is stirred at 200 ° for 1 hour. After the reaction is completed, ethyl acetate is added, the undissolved solution is filtered off with suction, the filtrate is concentrated and the residue is chromatographed on a 3 cm thick column of ethyl acetate with the addition of ethanol in a gradient. Several products are obtained, as a polar fraction 755 mg of 1- (2- [imidazol-1-yl] -cyclopenten-1-yl) -imidazole with a melting point of 85 °, as a non-polar fraction 340 mg of 1- (2-bromocyclopenten-1- yl) imidazole and almost the same as 1- (cyclopenten-1-yl) imidazole.
[1H] -NMR (CDCL3) of 1- (2-bromocyclopenten-1-yl) imidazole: 7.95, 7.45, 7.11 each s broad 1H of imidazole, 2.8 m 4H, 2.12 dtr 2H.
[1H] -NMR (CDCL3) of 1- (cyclopenten-1-yl) imidazole: 7.60, 7.06, 7.01 each broad 1H imidazole, 5.60 m 1 H cyclopentene, 2.75 m 4H, 2.43 dtr 2H.

Example 2 1- (2-methylthiocyclopenten-1-yl) imidazole

213 mg of 1- (2-bromocyclopenten-1-yl) imidazole are stirred with 105 mg of sodium thiomethylate in 3 ml of NMP at 100 to 1200 for 8 hours. Distribute the crude product between EE and water, wash the organic phase with brine, dry with magnesium sulfate and evaporate. Column chromatography with hexane / EE provides 130 mg of slightly contaminated product, which is cleaned of contaminants on the Kugelrohr.
[1H] -NMR (CDCL3): 7.83, 7.39, 7.10 each broad 1H imidazole, 2.74 and 2.83 m each 2H, 2.09 dtr 2H, 2.305 3H methyl.
In the same way, sodium thioethylate and sodium thioisopropoxide as well as sodium hydride and 2-methyl-1-mercaptopropan 1- (2-ethylthiocyclopenten-1-yl) imidazole and 1- (2- [prop-2-yl-thio] cyclopenten-1 -yl) -imidazole shown.

Example 3 1- (2- [pyrazol-1-yl] cyclopenten-1-yl) imidazole

0.21 gr of 1- (2-bromocyclopenten-1-yl) imidazole are dissolved in 0.5 ml of NMP, 1 equivalent of pyrazole, 1.1 equivalents of potassium carbonate and 30 mg of copper powder are added. After 2 hours at 200 °, ethyl acetate is added, the mixture is filtered off with suction and the precipitate is washed thoroughly, the filtrate is concentrated and chromatographed on a 2 cm thick column using ethyl acetate. 100 mg of product are obtained.
[1H] -NMR (CDCL3): 7.61 d 0.5 Hz, 7.42, 7.10 each s wide 1H imidazole, 7.07 d, 0.6 Hz 1H, 6.68 s wide 1H, 6.29 dd 1H, 3.1 and 2.9 m each 2H, 2.19 ddtr 2H.

You get analog
1- (2- [pyrrol-1-yl] cyclopenten-1-yl) imidazole
such as
1- (2- [1,2,4-triazol-1-yl] cyclopenten-1-yl) imidazole.

Example 4 1- (2- [2-thienyl] cyclopenten-1-yl) imidazole

1- (2-bromocyclopenten-1-yl) imidazole (213 mg) is mixed with 118 mg of tetrakis triphenylphosphine palladium (0) under protective gas in 3 ml of DME, 1.2 equivalents of 2-thiophene boronic acid (153.5 mg) and 255 mg of sodium hydrogen carbonate in 3 ml of water are added and the mixture is stirred at 100 ° for 4 hours. It is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated. Column chromatography with toluene / EA 1: 1 follows. The yield is 64%.
[1H] -NMR (CDCl₃): 7.50, 7.20, 7.205 d, 6.94 d, 6.93 s wide, 6.80 d, 2.94 and 2.82 each 2H, 2.15 ddtr 2H.

In the same way, 1- (2- [3-thienyl] -cyclopenten-1-yl) - imidazole is formed with 3-thiophene boronic acid in 68% yield.
[1H] -NMR (CDCl₃): 7.50, 7.19 dd, 7.14 d, 7.04 dd, 6.93 dd, 6.52 dd, 2.94H, 2.12 dtr 2H.

Analogously, 1- (2- [phenyl] cyclopenten-1-yl) imidazole is obtained with phenylboronic acid.

With 5-tributylstannyl-2,3-dihydrothiophene, 1- (2- [2,3-dihydrothiophene-5-yl] - cyclopenten-1-yl) imidazole.

Example 5 1- (2- [2-thienyl] cyclopenten-1-yl) imidazole oxalate

To 55 mg of 1- (2- [2-thienyl] cyclöpenten-1-yl) imidazole in 1.5 ml of ethanol p.a. become 22.8 mg Given oxalic acid (1 equivalent). After stirring for 3 hours at RT, the solution is put in the freezer. 34 mg of crystals and further product are obtained in the mother liquor. [1H] -NMR (DMSO): 7.95, 7.49 d, 7.30, 7.22, 7.02 dd, 6.94 d, 2.92 and 2.82 each 2H, 2.10 dtr 2H.

Analogously, 1- (2- [3-thienyl] cyclopenten-1-yl) imidazole oxalate is prepared.

Example 6 1- (2- [3-bromo] thienyl) imidazole and 1- (2- [3-imidazol-1-yl] thienyl) imidazole and 1- (2-thienyl) - Imidazole

2 equivalents of imidazole, 1.52 g of potassium carbonate and 50 mg of copper powder are added to 1.2 g of 2,3-dibromothiophene in a little NMP and the mixture is heated at 200 ° for 4 hours. After dilution with ethyl acetate, the product is filtered off with suction, rotated in and purified by means of column chromatography with hexane / EA. 19% of bromine compound and 21% of 1- (2- [3-imidazol-1-yl] thienyl) imidazole and 40% of 1- (2-thienyl) imidazole are obtained. Bromine compound: [1H] -NMR (CDCl₃): 7.75, 7.21, 7.18, 7.27 thiophene, 7.01 thiophene.
1- (2- (3-Imidazol-1-yl) thienyl) imidazole: [1H] -NMR (CDCl₃): 7.5 m 2H, 7.17 to 6.8 m 4H, 7.36, 7 , 13 1H each.
1- (2-thienyl) imidazole: In addition to the process described, 1- (2-thienyl) imidazole is also formed from 2-bromothiophene in good yield with the following [1H] -NMR (CDCl₃):
7.73, 7.2, 7.17 each 1H, 7.15 dd 5Hz / 1Hz, 7.00, 6.99 each 1H.

Example 7 1- (3- [4-bromo] thienyl) imidazole and 1- (3- [4-imidazol-1-yl] thienyl) imidazole

It is added to 1.8 g of 3,4-dibromothiophene in 2 ml of NMP, 0.68 g of imidazole, 1.52 g of potassium carbonate and 80 mg of copper powder, and the mixture is heated at 2000 for 2 hours. The mixture is diluted with ethyl acetate, suction filtered, and rotated and the column is purified by column chromatography with hexane / EA. There are 20% 1- (3 - [- bromo] thienyl) imidazole with the following [1H] -NMR (CDCl₃): 7.71 s wide, 7.18, 7.10, 7.42 d 1.5 Hz, 7 , 32 d 1.5 Hz; and 17% of 1- (3- [-imidazol-1-yl] thienyl) imidazole can be isolated.
([1H] -NMR (CDCl₃): 7.47, 7.11, 6.77 each 2H, 7.455 2H.
1- (2- [5-bromo] thienyl) imidazole and 1- (2- [5-imidazol-1-yl] thienyl) imidazole are obtained in an analogous procedure in 11% and 22% yield respectively.
[1H] -NMR of the bromine compound (CDCl₃): 7.70, 7.17, 7.15 each 1H, 7.00 d 4Hz and 6.79 d 4Hz thiophene-H.
[1H] -NMR of the bisimidazole compound: (CDCl₃): 7.77 m 2H, 7.2 m 4H, 6.92 s 2H thiophene-H.

The following are synthesized analogously:
1- (2- [4Brom] thienyl) imidazole and 1- (3- [5-bromo] thienyl) imidazole from 2,4-dibromothiophene each in 5-6% yield.
1- (2- (4-bromo) thienyl) imidazole: [1H] -NMR (CDCl₃): 7.74, 7.20 2H, 7.08 d, 6.97 d.
1- (3- [5-bromo] thienyl) imidazole [1H] -NMR (CDCl₃): 7.8, 7.25, 7.20, 7.15 d, 7.10 d.

This method also gives 1- (2- [4,5-dibromo] thienyl) imidazole from 2,3,5-tribromothiophene with [1H] -NMR (CDCl₃): 7.75, 7.22, 7, 17, 7.36 sharp s each 1H.
This also creates 1- (2- [3-bromo-5-imidazol-1-yl] thienyl) imidazole in variable proportions with [1H] -NMR (CDCl₃): 7.752H, 7.134H, 7.3 1H.

Likewise, 1- (2- [3,4-dibromo] thienyl) imidazole is obtained from 2,3,4-tribromothiophene.

Example 8 1- (2- [3-methylthio] thienyl) imidazole

0.75 mmol of sodium thiomethylate are slowly added to 101 mg of 1- (2- [3-bromo] thienyl) imidazole in 3 ml of NMP at RT. After 3 hours at 1000 the mixture is worked up: adding ethyl acetate and water, washing the organic phase with brine, drying with magnesium sulfate and rotating in. Column chromatography with ethyl acetate provides 85% product.
[1H] -NMR (CDCl₃): 7.72, 7.19 2H, 7.22 d 5 Hz, 7.0 d 5 Hz, 2.325 3H methyl.

Analogously, the reaction of 230 mg of 1- (3- [4-bromo] thienyl) imidazole with 70 mg of sodium thiomethylate in NMP gives 1- (3- [4-methylthio] thienyl) imidazole in 7% yield. Furthermore, 1- (3-thienyl) imidazole is formed in 16% yield.
[1H] -NMR (CDCl₃): 7.82, 7.25, 7.18, 7.42 dd, 7.19 dd, 7.18 dd.

Example 9 1- (2- [4-thiophene-2-yl] thienyl) imidazole

1- (2- [4-bromo] thienyl) imidazole (16 mg) is treated with 8.2 mg of tetrakis-triphenylphosphine-palladium (0) under protective gas in 0.3 ml of DME, 1.2 equivalents of thiophene-2- Boronic acid and 17 mg of sodium hydrogen carbonate in 0.3 ml of water are added and the mixture is stirred at 100 ° for 4 hours. It is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated. Column chromatography with hexane / EA 1: 1 follows. The yield is 86%.
[1H] -NMR (CDCl₃): 7.80, 7.3 to 7.2 m 5H, 7.17 d, 7.07 dd.

Analogously:
from 1- (2- [5-bromo] thienyl) imidazole
1- (2- [5-Thiophen-2-yl] thienyl) imidazole in 27% yield.
[1H] -NMR (CDCl₃): 7.78, 7.22, 7.19, 7.28 d 4Hz, 7.15 d, 7.05 d, 7.02 m, 6.92 m.

from 1- (3- [4-bromo] thienyl) imidazole
1- (3- [4-Thiophene-2-yl] thienyl) imidazole in a yield of 67%.
[1H] -NMR (CDCl₃): 7.56, 7.18, 6.99, 7.46 d 4 Hz, 7.38 d 4 Hz, 7.22 dd 5Hz / 0.8Hz, 6.93 dd, 6 , 55 dd.

with thiophene-3-boronic acid from 1- (3- [4-bromo] thienyl) imidazole
1- (3- [4-Thiophen-3-yl] thienyl) imidazole in 74% yield.
[1H] -NMR (CDCl₃): 7.54, 7.18, 6.97, 7.43 d 4 Hz, 7.35 d 4 Hz, 7.29 dd, 6.83 dd, 6.80 dd.

from 2,3-dibromothiophene with thiophene-2-boronic acid
2-thienyl-3-bromo-thiophene. The yield is 34%:
[1H] -NMR (CDCl₃): 7.43 dd, 7.39 dd, 7.20 d, 7.10 dd, 7.02 d each 1H.

From 2,3,5-tribromothiophene 2- (3-nitrophenyl) -4,5-dibromothiophene is produced with 3-nitrophenylboronic acid. The yield is 41%.
[1H] -NMR (CDCl₃): 8.33, 8.19, 7.80, 7.60, 7.25 each d or dd, each 1H.
In addition, there is a small proportion of 2- (3-nitrophenyl) -5-bromothiophene.
2,3,5-tribromothiophene is also reacted with p-chlorophenylboronic acid, with o, p-dichlorophenylboronic acid, with phenylboronic acid, with p-methylphenylboronic acid and others to give the corresponding products.

Example 10 5- (3-nitrophenyl) -3-bromo-2- (imidazol-1-yl) thiophene and 5- (3-4-Cl, 2,4-dichloro, 4- methylphenyl) -2,3-bis (imidazol-1-yl) thiophene

2- (3-nitrophenyl) -4,5-dibromothiophene is reacted with imidazole as described in Example 7. 21% of 5- (3-nitrophenyl) -3-bromo-2- (imidazol-1-yl) thiophene are obtained in addition to 5- (3-nitrophenyl) -2- (imidazol-1-yl) thiophene and 5- (3-nitrophenyl) -2,3-bis (imidazol-1-yl) thiophene.
5- (3-nitrophenyl) -2,3-bis (imidazol-1-yl) thiophene:
[1H] -NMR (CDCl₃): 8.45, 8.27, 7.9, 7.69, 7.59, 7.4 s, 7.2, 7.15, 6.99, 6.85 each 1H.
5- (3-nitrophenyl) -3-bromo-2- (imidazol-1-yl) thiophene:
[1H] -NMR (CDCl₃): 8.41, 8.20, 7.85, 7.63, 7.81, 7.26, 7.35 s, each 1H.

Analogously arise:
5-phenyl-3-bromo-2- (imidazol-1-yl) thiophene and 5-phenyl-2,3-bis (imidazol-1-yl) thiophene, 5- (4-chlorophenyl) -3-bromo- 2- (imidazol-1-yl) thiophene, 5- (2,4-dichlorophenyl) -3-bromo-2- (imidazol-1-yl) thiophene, 5- (4-methylphenyl) -3-bromo- 2- (imidazol-1-yl) thiophene.

Example 11

5- (3-Nitrophenyl) -3-bromo-2- (imidazol-1-yl) thiophene is obtained analogously to Example 9 with 2-thiophene boronic acid, 5- (3-nitrophenyl) -3- (2-thienyl) - 2- (imidazol-1-yl) thiophene with [1H] NMR (CDCl₃): 8.49 dd, 8.22 dd, 7.91 dd, 7.64 tr, 7.66 s broad, 7.28 s broad 2H, 7.56 s 1H, 7.28 d, 7.01 dd, 6.85 dd.
and with
3-thiophene boronic acid 5- (3-nitrophenyl) -3- (3-thienyl) -2- (imidazol-1-yl) thiophene.

Becomes analog
5-phenyl-3- (2-thienyl) -2- (imidazol-1-yl) thiophene and 5-phenyl-3- (3-thienyl) -2- (imidazol-1-yl) thiophene.

Example 12 1- (3- [4- (2,3-Dihydrothiophen-5-yl)] thienyl) imidazole

0.5 mmol of 1- (3- [4-bromo] thienyl) imidazole are mixed with 1.2 equivalents of 5- Tributylstannyl-2,3-dihydrothiophene in 5 ml toluene with the addition of bis- (triphenylphosphine) palladium chloride (0.03 mmol) and 2.5 mmol lithium chloride. After 8 Hours of reflux, filter off, concentrate and column chromatography gives this Product in 37% yield.

The following is prepared analogously: 1- (2- [3- (2,3-dihydrothiophen-5-yl)] thienyl) imidazole from 1- (2- (3-bromo) thienyl) imidazole.

Example 13 1- (3- [2-thiophene-2-yl] thienyl) imidazole

0.245 g of 2-thienyl-3-bromothiophene (see Example 9) in 1 ml of DMF are added to 82 mg of imidazole, 166 mg of potassium carbonate and 10 mg of copper powder, and the mixture is heated at 180 ° for 1 hour. The mixture is diluted with ethyl acetate, filtered off with suction, rotated in and the crude product is purified by column chromatography with hexane / EA 1: 1. Yield 53%.
[1H] -NMR (CDCl₃): 7.58, 7.21, 7.02, 7.29, 7.27, 7.02, 6.95, 6.90 each 1H.

Example 14 A.) 2-bromo-3-bromomethylthiophene

3.54 g of 2-bromo-3-methylthiophene (commercially available) are dissolved in 15 ml of carbon tetrachloride and refluxed for 1 hour with 3.91 g of N-bromosuccinimide and a knife tip of azoisobutyronitrile. It is diluted with dichloromethane, washed several times, dried the organic phase and concentrated. Column chromatography provides 42% product.
[1H] -NMR (CDCl₃): 7.27 d, 7.01 d, 4.46 s 2H.

Analogously, 2,5-dibromo-3-bromomethylthiophene is obtained from 2,5-dibromo-3-methylthiophene and from:
2-bromo-5-methylthiophene: 2-bromo-5-bromomethylthiophene
3-bromo-4-methylthiophene: 3-bromo-4-bromomethylthiophene.

B.) 2-bromo-3-methylthiomethylthiophene

512 mg of 2-bromo-3-bromomethylthiophene are stirred with 161 mg of sodium thiomethylate in 10 ml of NMP. After the reaction has been carried out, the mixture is diluted with water, extracted with ethyl acetate, washed several times, the organic phase is dried and concentrated. The raw product weighs 462 mg after drying and is suitable for further reactions.
[1H] -NMR (CDCl₃): 7.28 d, 6.98 d, 3.56 s 2H, 2.02 s 3H methyl.

Analogously, 2,5-dibromo-3-bromomethylthiophene and 2-bromo-5-bromomethylthiophene are obtained and 3-bromo-4-bromomethylthiophene almost quantitatively the corresponding methylthioethers.

C.) 2-bromo-3- (imidazol-1-yl) methylthiophene

2-bromo-3-bromomethylthiophene are reacted with 1 equivalent of imidazole, 1 equivalent of potassium carbonate for 3 hours at 120 °. After the usual work-up and column chromatography with ethyl acetate / ethanol, the product is obtained in 56% yield.
[1H] -NMR (CDCl₃): 7.56, 7.08, 6.93, broad s 1 H each of imidazole, 7.27 d, 6.72 d, 5.08 s 2H.

Analogously, 3-bromo-4 (imidazol-1-yl) methylthiophene is obtained from 3-bromo-4- bromomethylthiophene.

D.) 1- (3- [2-Methylthio] thiophenmethyl) imidazole

As described in Example 7, 2- (imidazol-1-yl) -3-methylthiomethylthiophene is synthesized from 2-bromo-3-methylthiomethylthiophene in 11% yield.
[1H] -NMR (CDCl₃): 7.7 s, 7.19 m 2H, 7.155 1H, 7.02 d 1H, 3.4952H, 2.035 3H.

The following is made analogously:
2- (Imidazol-1-yl) - [3- (Imidazol-1-yl) methyl] thiophene
2-bromo-3- (imidazol-1-yl) methylthiophene. Yield 9%
3-imidazolyl-4- (imidazol-1-yl) methylthiophene from 3-bromo-4- (imidazol-1-yl) methylthiophene.

Claims (6)

1. Compounds of formula I or Ia wherein
Z sulfur or -NH-,
A CH₂ or a bond,
R¹ phenyl or a 5-membered hetaryl radical with 1-3 N, O or S atoms, each with halogen, cyano, C _1-4 alkyl, NH₂, -N (C _1-4 allyl) ₂ or -NH (C _1-4 alkyl) may be substituted, halogen, S (O) m -CH₂R³ or OR⁴,
R² is hydrogen, optionally substituted with R phenyl, optionally substituted with R pyridinyl, halogen, cyano, NO₂, NH₂ or C _1-6 alkyl,
R = halogen, OH, NO₂, NH₂, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, NH (C _1-4 alkyl), -N (C _1-4 -Alkyl) ₂, NHSO₂-C _1-4 -alkyl, -COOH, -COOC _1-6 -alkyl, -CONHR⁵, -CF₃, -C (NH) -NHR⁶, -NH-C (NH) NHR⁷, -CH₂ -NHR⁸,
m = 0.1.2,
R³-R⁸ is the same or different hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-7 cycloalkyl and their isomers, tautomers and physiologically acceptable salts. 2. 1- (2-methylthiocyclopenten-1-yl) imidazole
1- (2- [2-thienyl] cyclopenten-1-yl) imidazole
1- (2- [3-methylthio] thienyl) imidazole
1- (2- [4-thiophene-2-yl] thienyl) imidazole. 3. A process for the preparation of the compounds of formula I and Ia according to claim 1, characterized in that

• a) a compound of formula II or IIa wherein
  -AR¹, R² and Z have the above meaning and Flu is a leaving group, in the presence of a base with imidazole, or
• b) a compound of formula III or IIIa wherein Z and A have the meaning given above and Hal represents halogen, substituted in the presence of a base or with an organometallic compound and then halogenated or selectively reduced if necessary or forming thioether or cleaving ether or saponifying nitriles or esterifying or amidating acids or etherifying from phenols or Esters are synthesized or amino groups are exchanged or boiled using the Sandmeyer reaction, or sulfides are oxidized to sulfones or sulfoxides, or sulfoxides are reduced to sulfides, or amines are converted to amides or sulfonamides, or alkylated or decarboxylated, or isomers are separated or salts are formed.

4. Use of the compounds according to claim 1 or 2 for the preparation of a Medicinal product for the treatment of diseases caused by nitric oxide synthases to be triggered. 5. Use according to claim 4 for the treatment of diseases of the center Nervous system.   6. Medicament containing a compound according to claim 1 or 2.